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PubMed2002

Prognostic value of angiogenesis in solitary bone plasmacytoma.

Angiogenesis plays an important role in the biology of multiple myeloma (MM) and has prognostic importance in this disease. Solitary plasmacytoma is a localized plasma cell malignancy that progresses to MM in a significant number of patients. We examined if angiogenesis is increased in solitary plasmacytoma and if it can help identify patients likely to progress to myeloma. We studied angiogenesis in plasmacytoma biopsy samples and bone marrow biopsies from 25 patients. High-grade angiogenesis was present in 64% of plasmacytomas. In contrast, bone marrow angiogenesis was low in all patients. Patients with high-grade angiogenesis in the plasmacytoma sample were more likely to progress to myeloma and had a shorter progression-free survival compared with patients with low-grade angiogenesis (P =.02). Angiogenesis is increased in solitary plasmacytoma and is a significant predictor of progression to myeloma and provides further evidence of its importance in the pathogenesis of myeloma.

Adult↗

PubMed2006

Dissecting the role of endothelial SURVIVIN DeltaEx3 in angiogenesis.

The identification of alternative splice variants of Survivin that possess distinct functions from those originally identified for the main Survivin isoform has greatly increased the complexity of our understanding of the role of Survivin in different cells. Previous functional studies of the Survivin splice variants have been performed almost exclusively in cancer cells. However, Survivin has increasingly been implicated in other normal physiologic and pathophysiologic processes, including angiogenesis. In this study, we dissect the involvement of Survivin DeltaEx3 in angiogenesis. We show by confocal microscopy that a pool of endothelial Survivin DeltaEx3 is localized to membrane ruffles. We also demonstrate that Survivin DeltaEx3 is the Survivin splice variant responsible for modulating angiogenesis in vitro, in tube formation assays, and in vivo, in an in vivo angiogenesis assay. Our data indicate that Survivin DeltaEx3 may regulate angiogenesis via several mechanisms including cell invasion, migration, and Rac1 activation. Our findings identify a novel pathway regulating angiogenesis through Survivin DeltaEx3 and a novel mechanism for Rac1 activation during angiogenesis. In conclusion, our results provide new insights into the regulation of endothelial cell homeostasis and angiogenesis by the Survivin proteins.

Alternative Splicing↗

PubMed1995

Clinical importance of the determination of tumor angiogenesis in breast carcinoma: much more than a new prognostic tool.

PURPOSE: To review prognostic and therapeutic applications of angiogenesis research in breast carcinoma. METHODS: We reviewed the (1) biologic role of angiogenesis, particularly in transformation, progression, and metastasis of breast cancer; (2) methods to detect angiogenic activity in human pathology; (3) clinical studies relating clinical outcome of patients with breast cancer to the assessment of angiogenesis; (4) predictive value of angiogenesis for response to anticancer therapies; and (5) pharmacologic characteristics of current antiangiogenic drugs. RESULTS: There is mounting evidence that angiogenesis plays a relevant role in the biologic aggressiveness of breast cancer. Using either immunohistochemical or biochemical methods, several studies have shown a worse prognosis for those patients with tumors with high angiogenic activity. In some studies angiogenesis has an independent prognostic value. The most promising angiogenic inhibitors are under early-phase clinical evaluation in patients with tumors resistant to conventional therapies. Novel therapeutic strategies for breast cancer patients are presented and discussed. CONCLUSION: The majority of the retrospective studies show that angiogenesis is an important new prognostic indicator in early-stage breast carcinoma. This marker should be evaluated in prospective controlled clinical trials to demonstrate whether adjuvant therapies may improve the prognosis of those patients at high risk, eg, those with highly vascularized tumors. Since invasive breast carcinoma has a well defined stromal vascular component and produces angiogenic factors, it seems reasonable to postulate that this tumor may be one of the most responsive to angiogenesis inhibitors given alone or in combination with conventional anticancer treatments.

Breast Neoplasms↗

PubMed2005

The role of mechanical stresses in angiogenesis.

Angiogenesis is the formation of new capillary blood vessels from preexisting vessels. It is involved in many normal and diseased conditions, as well as in the application of tissue-engineered products. There has been extensive effort made to develop strategies for controlling pathological angiogenesis and for promoting vascularization in biomedical engineering applications. Central to advancing these strategies is a mechanistic understanding of the angiogenic process. Angiogenesis is tightly regulated by local tissue environmental factors, including soluble molecules, extracellular matrices, cell-cell interactions, and diverse mechanical forces. Great advances have been made in identifying the biochemical factors and intracellular signaling pathways that mediate the control of angiogenesis. This review focuses on work that explores the biophysical aspect of angiogenesis regulation. Specifically, we discuss the role of cell-generated forces, counterforces from the extracellular matrix, and mechanical forces associated with blood flow and extravascular tissue activity in the regulation of angiogenesis. Because angiogenesis occurs in a mechanically dynamic environment, future investigations should aim at understanding how cells integrate chemical and mechanical signals so that a rational approach to controlling angiogenesis will become possible. In this regard, computational models that incorporate multiple epigenetic factors to predict capillary patterning will be useful.

Animals↗

PubMed2000

Heterogeneity of angiogenesis and blood vessel maturation in human tumors: implications for antiangiogenic tumor therapies.

Microvessel density (MVD) counting techniques have been widely used to assess the vasculature in tumors. MVD counts assess the presence of blood vessels but do not give an indication of the degree of angiogenesis and the functional status of the tumor neovasculature. To analyze angiogenesis and the functional status of the tumor vascular bed, we have quantitated endothelial cell proliferation and the recruitment of pericytes in human tumors [glioblastomas (n = 30), renal cell carcinomas (n = 22), colon carcinomas (n = 18), mammary carcinomas (n = 24), lung carcinomas (n = 15), and prostate carcinomas (n = 19)]. These findings were compared to the physiological angiogenesis in the cyclic bovine ovarian corpus luteum. Tissue sections were examined applying double-labeling immunohistochemical techniques to detect proliferating endothelial cells and to colocalize endothelial cells and pericytes. The following parameters were quantitated: (a) MVD count; (b) proliferating capillary index (PCI); (c) proliferating tumor versus endothelial cell index; and (d) microvessel pericyte coverage index (MPI). Based on endothelial cell proliferation, angiogenesis was found to be present in all tumors with characteristic and significant differences between the tumor types (glioblastomas, PCI = 9.6 +/- 6.1%; renal cell carcinomas, PCI = 9.4 +/- 5.2%; colon carcinomas, PCI = 7.8 +/- 5.2%; mammary carcinomas, PCI = 5.0 +/- 4.8%; lung carcinomas, PCI = 2.6 +/- 2.5%; prostate carcinomas, PCI = 2.0 +/- 1.4%). There was a considerable degree of heterogeneity in the intensity of angiogenesis within each tumor group, as indicated by large standard deviations. Even in the most angiogenic tumors, angiogenesis was found to be 4 to 20 times less intense as compared with the physiological angiogenesis in the growing ovarian corpus rubrum (PCI = 40.6 +/- 6.2%). Varying degrees of pericyte recruitment to the tumor microvasculature were determined in the different tumor types (glioblastomas, MPI = 12.7 +/- 7.9%; renal cell carcinomas, MPI = 17.9 +/- 7.8%; colon carcinomas, MPI = 65.4 +/- 10.5%; mammary carcinomas, MPI = 67.3 +/- 14.2%; lung carcinomas, MPI = 40.8 +/- 14.5%; prostate carcinomas, MPI = 29.6 +/- 9.5%). The data demonstrate distinct quantitative variations in the intensity of angiogenesis in malignant human tumors. Furthermore, the varying degrees of pericyte recruitment indicate differences in the functional status of the tumor vasculature in different tumors that may reflect varying degrees of maturation of the tumor vascular bed.

Animals↗

PubMed2000

Fibroblast growth factors are required for efficient tumor angiogenesis.

Although the function of vascular endothelial growth factor in the induction of tumor angiogenesis is well understood, the role of a second group of angiogenic factors, the fibroblast growth factors (FGFs), remains elusive. We used a recombinant adenovirus expressing soluble FGF receptor (AdsFGFR) to interfere with FGF function in tumor angiogenesis. AdsFGFR repressed endothelial cell proliferation in vitro and inhibited tumor angiogenesis in an ex vivo bioassay, in which endothelial cells were cocultured with angiogenic tumor biopsies in a collagen gel. Moreover, AdsFGFR repressed tumor angiogenesis and hence tumor growth in vivo in allograft transplantation experiments. Whereas adenoviral expression of a soluble form of VEGF receptor 1 (AdsFlt) predominantly affected the initiation of tumor angiogenesis, soluble FGF receptor (sFGFR) appeared to impair the maintenance of tumor angiogenesis. The combination of sFGFR and soluble Flt exhibited a synergistic effect in the repression of tumor growth. Finally, i.v. injection of AdsFGFR resulted in a dramatic repression of tumor growth in a transgenic mouse model of pancreatic beta cell carcinogenesis. Similar to control infections with AdsFlt, tumor-associated vessel density was decreased, indicating that the expression of sFGFR impaired tumor angiogenesis. These data indicate that FGFs play a critical role in tumor angiogenesis.

Adenoviridae↗

PubMed2000

[Expression of transforming growth factor beta 1 (TGF beta 1) and angiogenesis in broncho-pulmonary carcinoids].

TGF beta 1 commonly produced by normal and neoplastic human cells, has capacity to regulate new blood vessel formation, to establish and maintain the vessel wall integrity; was found to have some significance in the lung cancer prognosis. Tumour angiogenesis is an important factor for tumour growth and metastasis. The purpose of this study was to find, if the immunoexpression of TGF beta 1 has any significance in determination of the histologic subtypes of carcinoids?; to find, if TGF beta 1 has any role and relation to carcinoids angiogenesis?; and to explore TGF beta 1 expression and angiogenesis with respect to metastatic potential of carcinoids. The study was performed on 48 resected broncho-pulmonary carcinoids: 35 typical (TC) and 13 atypical (AC), classified according to the WHO. Semiquantitative analysis for TGF beta 1 was performed. Sections stained using monoclonal antibody against TGF beta 1 were scored in scale from 0 to 4, according to the percentage of positively stained cells (pc) plus percentage of positively stained stroma (ps). The microvessels stained with CD34 monoclonal antibody, were counted in 0.75 mm2 field (microvessel density--MD), using the computerised image analysis system SAMBA 2005 (the morphometric software). The histologic subtype of carcinoids was related to age of the pts (AC occurred in older pts than TC, p = 0.027), to the tumour size (AC were larger than TC: respectively--3.25 cm and 2.4 cm, p = 0.009). Lymph node metastases were significantly more frequent in AC than in TC (38% vs 13%, p = 0.025). 85% carcinoids showed TGF beta 1 expression with various intensity, mainly in the stroma. There was no significant correlation between TGF beta 1 expression and tumour size, the histologic subtype nor the lymph node metastases. The angiogenesis expressed as MD, was not related to histology, nor to the presence of lymph node metastases. There was no correlation between TGF beta 1 expression and angiogenesis. Shown in our study, lack of relation between TGF beta 1 expression and angiogenesis, could support some of the published data indicating indirect action of TGF beta 1 on the angiogenesis. The rich vascularity found in carcinoids morphology could result from TGF beta 1, commonly expressed by the tumoural stroma. The angiogenesis nor TGF beta 1 expression do not determinate the carcinoids histology.

Adult↗

PubMed2005

Inhibition of gastric cancer angiogenesis by vector-based RNA interference for Raf-1.

Tumor angiogenesis plays an important role in the malignancy of solid tumors. A number of recent studies including our own have suggested that Raf-1 is involved in this process, and may be critical in regulating gene activation of several angiogenesis factors. To further define Raf-1 function in angiogenesis and to explore novel approaches to modulate angiogenesis, we employed the small interference RNA technique to knock-down gene expression of Raf-1 in gastric cancer cell line SGC7901 that expresses a high level of Raf-1. The protein level of Raf-1 in the SGC7901cells was decreased dramatically after transfection with a Raf-1 specific siRNA vector. Further study proved that, VEGF and HIF-1alpha, two angiogenesis promoting factors, were found to be downregulated. And we also find that Vector-based RNA interference for Raf-1 increases transfected gastric cell apoptosis and inhibits cellular proliferation. Our results suggest that Raf-1 may be involved in angiogenesis by controlling the expression of angiogenesis-related factors and provide a possible strategy for the treatment of tumor angiogenesis by targeting Raf-1.

Down-Regulation↗

PubMedDate not supplied

[Angiogenesis in cancer and its detection with radiolabeled biomolecules].

The present article refers to the mechanism of angiogenesis, a phenomenon which in certain cases is normal, however it usually accompanies the formation of solid cancerous tumors. During the process of angiogenesis, migration, differentiation and proliferation of endothelial cells occurs. In some pathological cases, the most important of which is cancer, the mechanism of angiogenesis is reinforced. It has been observed that a tumor cannot grow without the formation of new blood vessels in the surrounding tissues, which account for blood supply to the tumor. The process of angiogenesis is regulated by chemical signals of the organism, which function as an "angiogenesis switch" regulating the formation of new vasculature. A variety of anti-angiogenic agents which lead to angiogenesis inhibition are found in the clinical trial phase. Among these agents are: i) molecules which inhibit the action of Vascular Endothelial Growth Factors, VEGF, ii) molecules which obstruct migration, differentiation and proliferation of endothelial cells, via their binding to receptors of the alpha(nu)beta(3) integrins and iii) inhibitors of metalloproteinases (MMP). Certain molecules of the above mentioned categories, labeled with radionuclides which emit gamma- radiation or beta- particles or positrons, have been proposed and are being evaluated as possible radiopharmaceuticals, for the visualization of receptors involved in the mechanism of angiogenesis, aiming at the scintigraphic detection of primary or metastatic cancer at an early stage and possibly, aiming at its inhibition/treatment. Regarding the study of angiogenesis the following have been described: a. antibodies targeting VEGF, labeled with radionuclides emitting beta- and/or gamma-radiation, which can be applied for the diagnosis and possibly, for the treatment of cancer, b. peptide derivatives which contain the amino-acid sequence RGD (Arg-Gly-Asp) and compete for the alpha(nu)beta(3) integrins, with the proteins of the stroma. It has been found that these radiolabeled derivatives localize in tumors and can be used for the visualization and, possibly, for the tumor eradication of primary and metastatic cancer.

Animals↗

PubMed1990

Wound healing angiogenesis: indirect stimulation by basic fibroblast growth factor.

Basic fibroblast growth factor (bFGF) was tested for its ability to stimulate angiogenesis in vivo using the rabbit corneal assay. Basic FGF (50-1,000 ng) was incorporated into 10% Hydron, and 50-500 ng of bFGF were incorporated into 10% Elvax. Human serum albumin (HSA) (10 ng) and 50 ng of transforming growth factor-beta (TGF-beta) served as negative and positive controls. Pellets of the polymers containing test compounds were implanted in the rabbit cornea, examined daily, and after 7 days corneal angiogenesis was scored on a graded scale [(-) for no response and +4 for a maximum response]. Histologic analysis of the corneas was performed on days 2 and 7. Basic FGF (50-500 ng) in Hydron failed to stimulate significant angiogenesis, though it did induce angiogenesis accompanied by inflammation at the 1,000-ng dose. Basic FGF in Elvax elicited inflammation-associated +3 to +4 responses at all doses tested. New blood vessels did not form in response to HSA in Hydron or Elvax, while TGF-beta induced +4 angiogenesis accompanied by vigorous inflammation. In vivo release kinetics for bFGF in Hydron and Elvax were compared, and the release of bioactive bFGF from Hydron and Elvax was demonstrated in vitro. These results suggest that the bFGF and Elvax combination incites an inflammatory response which stimulates indirect angiogenesis, while the same concentrations of bFGF delivered in Hydron produced no inflammation or angiogenesis. Although bFGF alone is a potent mitogen for endothelial cells, it does not appear to directly stimulate in vivo angiogenesis.

Animals↗

PubMed1990

Endothelial cell growth: biology and pharmacology in relation to angiogenesis.

The vascular system is lined by a monolayer of endothelial cells which proliferate very slowly under normal conditions. The formation of new capillary vessels is associated with some physiological circumstances and several pathological conditions. Angiogenesis requires migration, differentiation and proliferation of endothelial cells. The mechanism of tube formation is still poorly understood. Tumour growth is angiogenesis-dependent and angiogenesis is directly or indirectly induced by the tumour. Induction of angiogenesis is an important step in carcinogenesis and in metastatic development. Angiogenesis is induced during the transition from hyperplasia to neoplasia. Numerous angiogenic factors have been identified, most are mitogenic for endothelial cells and some are only responsible for tube formation. However, it is difficult to recognize which factor is the most important in vivo. Since angiogenesis is necessary for tumour growth, any natural or synthetic antiangiogenic compound may have an antineoplastic potential. Inhibition of tumour angiogenesis under the control of a tumour suppression gene could play an important role. Pharmacological compounds, such as heparin, heparin fragments and corticosteroids, have been shown to be antiangiogenic substances. More recently two new inhibitors of capillary endothelial cell proliferation and/or angiogenesis have been described: they are a cartilage-derived inhibitor and platelet factor 4.

Animals↗

PubMed1996

A novel in vitro assay for human angiogenesis.

Angiogenesis, the development of new blood vessels, is an important process in tissue development and wound healing but becomes pathologic when associated with solid tumor growth, proliferative retinopathies, and rheumatoid arthritis. To date, there has not been a physiologically relevant in vitro model for human angiogenesis that can be used to screen for enhancers and inhibitors of human angiogenesis and allow further investigation of this process. Initially, culture conditions were established for the induction of human angiogenesis in vitro using fragments of human placental blood vessel. Once the assay was validated, it was examined for its ability to detect known inhibitors and enhancers of angiogenesis. The role of endogenous acidic fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF) in the angiogenic response was also assessed by performing RT-PCR on both the parent vessel and microvessel outgrowths. In addition, neutralizing antibodies against the three growth factors were used to quantify the relative importance of each growth factor in the angiogenic response. A fragment of human placental blood vessel was embedded in a fibrin gel in microculture plates and was found to give rise to a complex network of microvessels during a period of 7 to 21 days in culture. The response did not require the addition of exogenous growth factors, and thus provides a convenient system for testing substances for their ability to stimulate or inhibit a human in vitro angiogenic response. The ability of the well known angiogenesis antagonist, hydrocortisone, in the presence and absence of heparin, and suramin to significantly inhibit the angiogenic response indicated that the model could be used as an efficient in vitro assay for screening inhibitors of human angiogenesis. The presence of mRNA for aFGF, bFGF, and three isoforms of VEGF, as well as their receptors, FGFR1, FGFR2, Flt-1, and KDR, in vessel outgrowths and the parent vessel, as identified by RT-PCR, strongly implicated aFGF, bFGF, and VEGF as having an important role in this neovascularization response. This was further confirmed by the ability of neutralizing antibodies to aFGF, bFGF, and VEGF to inhibit the angiogenic response to varying extent. Furthermore, the response could be enhanced by the addition of these growth factors in serum-starved cultures. Finally, a stimulatory effect was observed when matrigel was incorporated into the fibrin gel, which indicates that components of the extracellular matrix also play an important role in governing the strength of the angiogenic response. A physiologic angiogenic response relevant to wound healing can be generated by culturing fragments of human placental blood vessels in fibrin gels. The growth factors aFGF, bFGF, and VEGF were shown to play an important role in stimulating this spontaneous angiogenic response. This assay, which can be performed in microcultures, was also shown to be an excellent method for screening for potential inhibitors and enhancers of human angiogenesis.

Animals↗

PubMed1998

Pharmacological effects of SB 220025, a selective inhibitor of P38 mitogen-activated protein kinase, in angiogenesis and chronic inflammatory disease models.

Chronic inflammatory diseases often are accompanied by intense angiogenesis, supporting the destructive proliferation of inflammatory tissues. A model of inflammatory angiogenesis is the murine air pouch granuloma, which has a hyperangiogenic component. In this model, we explored the regulation of inflammatory angiogenesis using SB 220025, a specific inhibitor of human p38 mitogen-activated protein (MAP) kinase, with an IC50 value of 60 nM and 50- to 1000-fold selectivity vs. other kinases tested. In vivo, this compound reduced the lipopolysaccharide-induced production of tumor necrosis factor at an ED50 value of 7.5 mg/kg. In the inflammatory angiogenesis model, over the course of granuloma development, we observed elevated levels of interleukin-1beta and tumor necrosis factor-alpha during the chronic inflammatory phase when intense angiogenesis occurs. SB 220025 at 30 mg/kg b.i.d. p.o. was able to greatly reduce the expression of these cytokines and inhibit angiogenesis by approximately 40%. To further study the effects of p38/CSBP MAP kinase inhibition in angiogenesis-dependent chronic inflammatory disease, SB 220025 was tested in murine collagen-induced arthritis. In this model, SB 220025 was able to prevent the progression of established arthritis. Thus, this p38/CSBP MAP kinase inhibitor, which can reduce inflammatory cytokine production and inhibit angiogenesis, is an effective treatment for chronic proliferative inflammatory disease.

Animals↗

PubMed2005

Novel action of gastric proton pump inhibitor on suppression of Helicobacter pylori induced angiogenesis.

BACKGROUND: Although activation of mitogen activated protein kinases (MAPKs) by Helicobacter pylori infection is associated with induction of host angiogenesis, which may contribute to H pylori associated gastric carcinogenesis, the strategy for its prevention has not been identified. As we previously reported a strong inhibitory action of gastric proton pump inhibitors (PPIs) on MAPK extracellular signal regulated kinase (ERK)1/2 phosphorylation, we investigated whether PPIs could suppress the H pylori induced angiogenesis via inhibition of MAPK ERK1/2. METHODS: To address the relationship between H pylori infection and angiogenesis, comparative analysis of density of CD34(+) blood vessel was performed in tissues obtained from 20 H pylori positive gastritis and 18 H pylori negative gastritis patients. Expression of hypoxia inducible factor 1 (HIF-1alpha) and vascular endothelial growth factor (VEGF) was tested by reverse transcription-polymerase chain reaction and secretion of interleukin 8, and VEGF was measured by ELISA. To evaluate the direct effect of H pylori infection on the tubular formation of human umbilical vein endothelial cells (HUVEC), an in vitro angiogenesis assay was employed. Activation of MAPK and nuclear factor kappaB (NFkappaB) was detected by immunoblotting. RESULTS: H pylori positive gastritis patients showed a higher density of CD34(+) blood vessels (mean 40.9 (SEM 4.4)) than H pylori negative gastritis patients (7.2+/-0.8), which was well correlated with expression of HIF-1alpha. Conditioned media from H pylori infected gastric epithelial cells directly induced tubular formation of HUVEC and the increase of in vitro angiogenesis was suppressed by PPI treatment. Infection of H pylori significantly upregulated expression of HIF-1alpha and VEGF in gastric epithelial cells and expression of proangiogenic factors was mediated by MAPK activation and partially responsible for NFkappaB activation. PPIs effectively inhibited the phosphorylation of MAPK ERK1/2 that is a principal signal for H pylori induced angiogenesis. CONCLUSIONS: The fact that PPIs could downregulate H pylori induced angiogenesis indicates that antiangiogenic treatment using a PPI could be a promising protective therapeutic approach for H pylori associated carcinogenesis.

Adult↗

PubMed1993

Therapeutic angiogenesis.

We have proposed the term "therapeutic angiogenesis" to describe the induction or stimulation of neovascularization for the treatment or prevention of pathological clinical situations characterized by local hypovascularity. Evidence also shows that "clinically normal" healing and tissue regeneration can be improved or accelerated by therapeutic angiogenesis. Traditionally, therapeutic angiogenesis has been achieved by surgical methods, ie, the transposition of autologous tissues with uncompromised vasculature and high angiogenic potential such as omentum majus flaps and muscle flaps. Recent advances in the understanding of the biological process of neovascularization as well as the discovery and cloning of angiogenic cytokines may add a new clinical tool: therapeutic angiogenesis by pharmaceutical methods. Based on the results of animal studies and preliminary clinical trials, this review is aimed to give a state-of-the-art compilation of (1) those angiogenesis factors that appear promising in clinical application for therapeutic angiogenesis and (2) the surgical indication fields with near-term potential for therapeutic angiogenesis by use of angiogenic cytokines.

Angiogenesis Inducing Agents↗

PubMed2000

Targeting angiogenesis inhibits tumor infiltration and expression of the pro-invasive protein SPARC.

The solid growth of high-grade glioma appears to be critically dependent on tumor angiogenesis. It remains unknown, however, whether the diffuse infiltration of glioma cells into healthy adjacent tissue is also dependent on the formation of new tumor vessels. Here, we analyze the relationship between tumor angiogenesis and tumor cell infiltration in an experimental glioma model. C6 cells were implanted into the dorsal skinfold chamber of nude mice, and tumor angiogenesis was monitored by intravital fluorescence videomicroscopy. Glioma infiltration was assessed by the extent of tumor cell invasion into the adjacent chamber tissue and by expression of SPARC, a cellular marker of glioma invasiveness. To test the hypothesis that glioma angiogenesis and glioma infiltration are codependent, we assessed tumor infiltration in both the presence and the absence of the angiogenesis inhibitor SU5416. SU5416 is a selective inhibitor of the VEGF/Flk-1 signal-transduction pathway, a critical pathway implicated in angiogenesis. Control tumors demonstrated both high angiogenic activity and tumor cell invasion accompanied by strong expression of SPARC in invading tumor cells at the tumor-host tissue border. SU5416-treated tumors demonstrated reduced vascular density and vascular surface in the tumor periphery accompanied by marked inhibition of glioma invasion and decreased SPARC expression. A direct effect of SU5416 on glioma cell motility and invasiveness was excluded by in vitro migration and invasion assays. These results suggest a crucial role for glioma-induced angiogenesis as a prerequisite for diffuse tumor invasion and a possible therapeutic role for anti-angiogenic compounds as inhibitors of both solid and diffuse infiltrative tumor growth.

Angiogenesis Inhibitors↗

PubMed2003

Angiogenesis in pituitary adenomas.

Angiogenesis, which is the formation of new blood vessels from preexisting capillaries, plays an important role in tumor growth and metastasis. In this review, the focus is on angiogenesis in pituitary adenomas. Angiogenesis of pituitary adenomas has been assessed by studying tumor microvessel density using specific immunohistochemical markers to clarify the relationship between angiogenesis and tumor behavior. Unlike other organs, pituitary adenomas have significantly lower vascular densities as compared to nontumorous adenohypophysis, suggesting that the lack of significant angiogenesis may play a role in the slow pace of pituitary tumor growth and rarity of metastases. In addition, the relationship between microvessel density and various factors in pituitary adenomas is reviewed, including tumor types, age and sex, invasiveness, malignancy, several proliferative markers (MIB-1 or Ki-67). However, further studies will be needed, since many studies have reached opposite conclusions. Angiogenesis is a complex multistep process and several factors are found to be involved in each step of neovascularization, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and various other cytokines. VEGF and bFGF (or FGF-2), which are the most potent angiogenesis inducers among them, have been studied by immunohistochemistry, in situ hybridization, or in vitro studies in normal or adenomatous pituitaries and these results are also discussed in this review.

Adenoma↗

PubMed2003

Angiogenesis in normal and neoplastic pituitary tissues.

Angiogenesis, or the formation of new blood vessels, is a dynamic process needed for embryogenesis, post-natal growth, morphogenesis, tumorigenesis, and for other biological processes. Angiogenesis is very important for tumor development and progression. This review examines the activators and inhibitors of angiogenesis with emphasis on the pituitary gland and pituitary neoplasms. Some of the proteins regulating angiogenesis in pituitary tumors such as vascular endothelial growth factor (VEGF) and VEGF receptors, fibroblasts growth factors (FGF), transforming growth factor beta (TGFB), interleukins, interferons, and matrix metalloproteinases (MMPs) and inhibitors of MMPs have been examined in animal and human pituitary tumor models. However, many other significant regulators of angiogenesis including angiopoietins, angiostatin, and thrombospondins have not been studied extensively in pituitary tumors to date. Newer concepts and developments in angiogenesis such as vasculogenic mimicry and gene therapy approaches to angiogenesis in cancer treatment are also discussed.

Angiogenesis Inhibitors↗